Inhibition of interleukin-2 production by tumor cell products and by CKS-17, a synthetic retroviral envelope peptide.
Tumor cells of all types and species tested have been found to produce, in culture, substances that depress the expression of cell-mediated immunity, in the form of delayed-type hypersensitivity reactions in mouse feet. The factors responsible appear related immunologically to the retroviral envelope protein p15E. We have measured the effects of tumor products and conjugates of a p15E-related peptide, CKS-17, on interleukin-2 (IL-2) production by cultured, mitogen-stimulated EL4 cells; in this system IL-2 production is independent of IL-1. Supernatants of cultures of mouse, human and guinea-pig tumor cells inhibited IL-2 production in a dose-dependent fashion. CKS-17 conjugates, but not control conjugates, also inhibited IL-2 production. Responses to IL-2 of the CTLL line used were less inhibited by tumor products and very slightly inhibited by CKS-17 conjugates. IL-2 receptor density, assayed by flow cytometry, was not inhibited. IL-2 production was inhibited whether the tumor products or CKS-17 conjugates were added early or late in the course of culture of stimulated EL4 cells. Inhibition by CKS-17 conjugates was selective in that IL-2 production was inhibited to a greater degree than general protein synthesis in EL4 cells, and general protein synthesis by fibroblasts was unaffected. Measurement of IL-2 mRNA suggested that inhibition of IL-2 production was mediated post-transcriptionally. Fractionation of six different tumor supernatants on Sephacryl S-300 revealed a single peak of activity with an apparent molecular mass of 18 kDa. Antibodies to CKS-17 conjugates neutralized the inhibitory effect of native tumor products on IL-2 production. Inhibition of IL-2 production, by factors related to p15E, provides a strategically effective means of subversion of host defenses by tumors, and abrogation of this inhibition by means of antibodies might promote host resistance to tumor growth.
Nelson
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Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
Nelson
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D000818:Animals; D002455:Cell Division; D003208:Concanavalin A / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009363:Neoplasm Proteins / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000032:analysis; D015682:Retroviridae Proteins, Oncogenic / Q000494:pharmacology*; D013491:Suppressor Factors, Immunologic / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014759:Viral Envelope Proteins / Q000494:pharmacology*
D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; D009363:Neoplasm Proteins; D010455:Peptides; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D015682:Retroviridae Proteins, Oncogenic; D013491:Suppressor Factors, Immunologic; D014759:Viral Envelope Proteins; D003208:Concanavalin A; D003513:Cycloheximide; C053692:CKS 17